# US 9,434,785 B1 · Anti-human OX40L antibodies and methods of treating graft versus host disease with the same

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- Number: US 9,434,785 B1
- Document ID: US9434785B1
- Status: Granted
- Kind: B1
- Application number: 14/935,937
- Filed: 2015-11-09
- Granted: 2016-09-06
- Earliest claimed: 2015-04-30
- Assignees: Kymab Limited
- Applicants: Kymab Limited
- Inventors: Philip Bland-Ward; Jamie Campbell; Steve Holmes; Ian Kirby; Miha Kosmac; Leslie Susan Kean; Victor Tkachev
- Web page: https://patentgrep.com/patent/US9434785B1

## CPC

- C07K 16/2875: {against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 (against NGF C07K16/22, against TNF C07K16/241)}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- G01N 33/4833: {of solid biological material, e.g. tissue samples, cell cultures (tissue in vivo A61B5/00; cell suspensions G01N33/48735)}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/55: Fab or Fab'
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/624: Disulfide-stabilized antibody (dsFv)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/90: characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates to anti-human OX40L antibodies, new medical uses and methods.

## Claims

### Claim 1

A method of treating or preventing graft versus host disease (GvHD) in a human subject in need thereof, comprising:
administering an anti-OX40L antibody or fragment thereof that antagonizes specific binding of OX40 to OX40L to a subject determined to have a ratio of CD45RA+CCR7+CD95+OX40+ T stem cell memory (Tscm) cells to CD45RA+CCR7+CD95− T-naive (Tn) cells greater than 50:50 wherein the antibody or fragment thereof is administered in an amount effective to reduce the ratio of said Tscm cells in said human, wherein a blood sample obtained from the human subject has been subjected to an assay to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95− Tn cells in the sample.

### Claim 2 (depends on 1)

The method of claim 1, further comprising a step of assaying the blood sample obtained from the human subject to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95− Tn cells in the blood sample.

### Claim 3 (depends on 2)

The method of claim 2, wherein the assay comprises flow cytometry.

### Claim 4 (depends on 1)

The method of claim 1, wherein the ratio is greater than 60:40, or greater than 70:30, or greater than 75:25, or greater than 80:20, or greater than 85:15, or greater than 90:10, or greater than 95:5.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antibody or antibody fragment is humanized, human antibody or antibody fragment.

### Claim 6 (depends on 1)

The method of claim 1, wherein the antibody or antibody fragment is selected from the group consisting of:
multispecific antibodies, bi-specific antibodies, single-chain Fv antibodies (scFv), camelized antibodies, Fab fragments, F(ab′) fragments, disulfide-linked Fvs (sdFv), and epitope-binding fragments thereof.

### Claim 7

A method of treating or preventing graft versus host disease (GvHD) in a human subject in need thereof, comprising: administering an anti-OX40L antibody or fragment thereof that antagonizes specific binding of OX40 to OX40L to a subject determined to have a ratio of CD45RA+CCR7+CD95+OX40+ T stem cell memory (Tscm):CD45RA+CCR7+CD95− T-naive (Tn) cells greater than 50:50 wherein the antibody of fragment thereof is administered in an amount effective to reduce the ratio of said Tscm cells in said human, wherein the antibody or antibody fragment competes for binding of OX40L with an antibody comprising the VH sequence of SEQ ID NO: 34 and the VL sequence of SEQ ID NO: 48.

### Claim 8 (depends on 1)

The method of claim 1, wherein the antibody or antibody fragment thereof comprises a HCDR3 of from 16 to 27 amino acids and derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the human JH gene segment is IGHJ6 or IGHJ6*02.

### Claim 9 (depends on 1)

The method of claim 1, wherein the antibody or antibody fragment thereof comprises a CDR selected from:
a. the HCDR3 of antibody comprising variable regions Seq ID No:40 or Seq ID No: 46;
b. the HCDR3 of antibody comprising variable regions Seq ID No:8 or SEQ ID No: 14;
c. the HCDR3 of antibody comprising variable regions Seq ID No:72 or Seq ID No: 78;
d. the HCDR3 of antibody comprising variable regions Seq ID No:100 or Seq ID No:106;
e. an HCDR3 of any of the antibodies having the variable region amino acid sequence of Seq ID Nos: 215, 217, 219, 221, 223, 225, 227, 229 or 230; and
f. an HCDR3 of any of the antibodies having the variable region amino acid sequence of Seq ID Nos: 232 or 234.

### Claim 10 (depends on 1)

The method of claim 1, wherein the antibody or antibody fragment thereof comprises:
a. the CDRs of Seq ID No:40 or Seq ID No:46 for CDRH3, SEQ ID No:38 or SEQ ID No:44 for CDRH2, SEQ ID No:36 or SEQ ID No:42 for CDRH1, SEQ ID No:50 or SEQ ID No:56 for CDRL1, SEQ ID No:52 or SEQ ID No:58 for CDRL2 and SEQ ID No:54 or SEQ ID No:60 for CDRL3;
b. the CDRs of Seq ID No:8 or SEQ ID No:14 for CDRH3, SEQ ID No:6 or SEQ ID No:12 for CDRH2, SEQ ID No:4 or SEQ ID No:10 for CDRH1, SEQ ID No:18 or SEQ ID No:24 for CDRL1, SEQ ID No:20 or SEQ ID No:26 for CDRL2 and SEQ ID No:22 or SEQ ID No:28 for CDRL3;
c. the CDRs of Seq ID No:72 or Seq ID No:78 for CDRH3, SEQ ID No:70 or SEQ ID No:76 for CDRH2, SEQ ID No:68 or SEQ ID No:74 for CDRH1, SEQ ID No:82 or SEQ ID No:88 for CDRL1, SEQ ID No:84 or SEQ ID No:90 for CDRL2 and SEQ ID No:86 or SEQ ID No:92 for CDRL3;
d. the CDRs of Seq ID No:100 or Seq ID No:106 for CDRH3, SEQ ID No:98 or SEQ ID No:104 for CDRH2, SEQ ID No:96 or SEQ ID No:102 for CDRH1, SEQ ID No:110 or SEQ ID No:116 for CDRL1, SEQ ID No:112 or SEQ ID No:118 for CDRL2 and SEQ ID No:114 or SEQ ID No:120 for CDRL3;
e. the heavy chain CDRs and the light chain CDRs of variable region amino acid sequences
SEQ ID NO: 215 and SEQ ID NO: 214;
SEQ ID NO: 217 and SEQ ID NO: 216;
SEQ ID NO: 219 and SEQ ID NO: 218;
SEQ ID NO: 221 and SEQ ID NO: 220;
SEQ ID NO: 223 and SEQ ID NO: 222;
SEQ ID NO: 225 and SEQ ID NO: 224;
SEQ ID NO: 225 and SEQ ID NO: 226;
SEQ ID NO: 227 and SEQ ID NO: 214;
SEQ ID NO: 229 and SEQ ID NO: 228; or
SEQ ID NO: 230 and SEQ ID NO: 214;
f. the heavy chain CDRs and the light chain CDRs of variable region amino acid sequences
SEQ ID NO: 232 and SEQ ID NO: 231; or
SEQ ID NO: 234 and SEQ ID NO: 233;
g. the VH and/or VL domains of Seq ID No:34 for VH and/or Seq ID No:48 for VL;
h. the VH and/or VL domains of Seq ID No:2 for VH and/or Seq ID No:16 for VL;
i. the VH and/or VL domains of Seq ID No:66 for VH and/or Seq ID No:80 for VL;
j. the VH and/or VL domains of Seq ID No:94 for VH and/or Seq ID No:108 for VL;
k. the VH domain and the VL domain of amino acid sequences
SEQ ID NO: 215 and SEQ ID NO: 214;
SEQ ID NO: 217 and SEQ ID NO: 216;
SEQ ID NO: 219 and SEQ ID NO: 218;
SEQ ID NO: 221 and SEQ ID NO: 220;
SEQ ID NO: 223 and SEQ ID NO: 222;
SEQ ID NO: 225 and SEQ ID NO: 224;
SEQ ID NO: 225 and SEQ ID NO: 226;
SEQ ID NO: 227 and SEQ ID NO: 214;
SEQ ID NO: 229 and SEQ ID NO: 228; or
SEQ ID NO: 230 and SEQ ID NO: 214; or
l. the VH domain and the VL domain of amino acid sequences
SEQ ID NO: 232 and SEQ ID NO: 231; or
SEQ ID NO: 234 and SEQ ID NO: 233.

### Claim 11

A method of treating or preventing graft versus host disease (GvHD) in a human subject in need thereof, comprising: administering an anti-OX40L antibody or fragment thereof that antagonizes specific binding of OX40 to OX40L to a subject determined to have a ratio of CD45RA+CCR7+CD95+OX40+ T stem cell memory (Tscm): CD45RA+CCR7+CD95− T-naive (Tn) cells greater than 50:50 wherein the antibody or fragment thereof is administered in an amount effective to reduce the ratio of said Tscm cells in said human, wherein the antibody comprises the VH sequence of SEQ ID No:215 and the VL sequence of SEQ ID No:214.

### Claim 12 (depends on 1)

The method of claim 1, further comprising administering to the human a further therapeutic agent, wherein the further therapeutic agent is independently selected from the group consisting of rapamycin, sirolimus, tacrolimus, ciclosporin, corticosteroids, methylprednisolone, methotrexate, mycophenolate mofetil, anti-CD28 antibodies, anti-IL12/IL-23 antibodies, ustekinumab, anti-CD20 antibodies, rituximab, anti-CD30 antibodies, brentuximab, CTLA4-Fc molecules, abatacept, CCR5 receptor antagonists maraviroc, anti-CD40L antibodies, anti-VLA4 antibodies, natalizumab, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, alemtuzumab, anti-CD45 antibodies, cyclophosphamide, anti-thymocyte globulins, anti-complement C5 antibodies, -eculizumab, anti-a4b7 integrin antibodies, vedolizumab, anti-IL6 antibodies, -tocilizumab, anti-IL2R antibodies, basilixumab, anti-CD25 antibodies, daclizumab, anti-TNFa/TNFa-Fc molecules, etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, and Vorinostat.

### Claim 13 (depends on 12)

The method of claim 12, wherein the further therapeutic agent is rapamycin or tacrolimus.

### Claim 14

A method of preventing or treating graft versus host disease, comprising:
a. obtaining at least two T-cell samples derived from a subject who has or is at risk of graft versus host disease, wherein said at least two T-cell samples comprise a first sample taken at a first time point and a second sample taken at a second time point after the time first sample has been taken,
b. determining levels of CD45RA+CCR7+CD95+OX40+ Tscm cells in said first and second samples;
c. treating said subject to reduce the proportion of CD45RA+CCR7+CD95+OX40+ Tscm cells compared to said second sample by administering an anti-OX40L antibody or antibody fragment thereof in an amount effective to reduce the levels of Tscm cells, when the level of Tscm cells in said second sample are elevated as compared to said first sample, in order to treat or prevent said graft versus host disease.

### Claim 15 (depends on 14)

The method of claim 14, wherein said first sample is collected:
i. before the onset of said graft versus host disease; or
ii. after the onset of said graft versus host disease; and
wherein said second sample is collected no longer than one month after the first sample.

### Claim 16 (depends on 15)

The method of claim 15, wherein the second sample is collected no longer than 1 week after the first sample.

### Claim 17 (depends on 15)

The method of claim 15, wherein the treatment is administered in step (c) when the levels of Tscm cells in said second sample are greater than double the levels as compared to said first sample.

### Claim 18 (depends on 15)

The method of claim 15, wherein a first administration of the antibody or antibody fragment is performed after the first sample is taken and before the second sample is taken.

### Claim 19 (depends on 15)

The method of claim 15, further comprising the steps of
d. obtaining a third T-cell sample derived from said subject after the second sample has been taken;
e. determining the level of CD45RA+CCR7+CD95+OX40+ Tscm cells in said third sample;
f. treating said subject to reduce the proportion of CD45RA+CCR7+CD95+OX40+ Tscm cells by administering an anti-OX40L antibody or antibody fragment thereof that specifically binds OX40L, when the levels of Tscm cells in said third sample are elevated as compared to said second or said first sample.

### Claim 20 (depends on 7)

The method of claim 7, wherein a blood sample obtained from the human subject has been subjected to an assay to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95− Tn cells in the sample.

### Claim 21 (depends on 7)

The method of claim 7, further comprising a step of assaying a blood sample obtained from the human subject to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95− Tn cells in the blood sample.

### Claim 22 (depends on 21)

The method of claim 21, wherein the assay comprises flow cytometry.

### Claim 23 (depends on 11)

The method of claim 11, wherein a blood sample obtained from the human subject has been subjected to an assay to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95− Tn cells in the sample.

### Claim 24 (depends on 23)

The method of claim 23, wherein the assay comprises flow cytometry.

### Claim 25 (depends on 11)

The method of claim 11, further comprising a step of assaying a blood sample obtained from the human subject to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95− Tn cells in the blood sample.

### Claim 26 (depends on 7)

The method of claim 7, wherein the further therapeutic agent is rapamycin or tacrolimus.

### Claim 27 (depends on 11)

The method of claim 11, wherein the further therapeutic agent is rapamycin or tacrolimus.

### Claim 28 (depends on 7)

The method of claim 7, wherein the ratio is greater than 60:40, or greater than 70:30, or greater than 75:25, or greater than 80:20, or greater than 85:15, or greater than 90:10, or greater than 95:5.

### Claim 29 (depends on 11)

The method of claim 11, wherein the ratio is greater than 60:40, or greater than 70:30, or greater than 75:25, or greater than 80:20, or greater than 85:15, or greater than 90:10, or greater than 95:5.

### Claim 30 (depends on 1)

The method of claim 1, wherein the antibody comprises the VH sequence of SEQ ID No:215 and the VL sequence of SEQ ID No:214.